Treatment of vitiligo

ABSTRACT

Disclosed herein is a novel method of treating vitiligo by using an excimer laser that emits light in the UVB range. The invention includes a method of incrementally increasing exposure of affected vitiligo areas with UVB laser light from an excimer laser to restore pigmentation to skin areas afflicted with vitiligo.

[0001] This application claims priority under 35 U.S.C. § 119 from theProvisional Application Ser. No. 60/184,971 filed Feb. 25, 2000,incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Vitiligo is a cutaneous disease in which there is a complete lossof pigment in localized areas of the skin. This loss of pigment resultsin the effected areas being completely white. This condition has apredilection for the skin around the mouth and the eyes. The result iscosmetically disfiguring, especially for dark skinned people.Furthermore, the depigmented skin is sun sensitive, and thus is subjectto sunburns and skin cancer. In sum, vitiligo is both cosmetically andpractically distressing to patients afflicted with the disease.

[0003] In normal skin, varying shades of brown are seen (depending on aperson's race) representing the pigment melanin. This pigment isproduced by a cell type known as a melanocyte. In vitiligo, there is anabsence of melanocytes in the areas afflicted with the disorder. Anabsence of melanocytes results in an absence of melanin pigment, andthus the melanin-free area is white. Normal skin responds to ultravioletlight with an increase in the brown pigment melanin (tanning).Specifically, ultraviolet radiation stimulates melanocytes toproliferate and produce more melanin.

[0004] Attempts have also been made to “tan” vitiligo areas usingultraviolet light treatments. The ultraviolet spectrum is divided intotwo portions, “UVA” and “UVB,” which is light of 320-400 nm and 290-320nm in wavelength, respectively. UVB is much more effective at producinga tan in normal skin. In normal skin, melanocytes reside in theepidermis, which is the outer layer of the skin. The epidermis is only0.1 mm thick, so the melanocytes are very near the surface. UVBradiation can only penetrate to about 0.1 mm, but this is sufficient toreach the melanocytes. In patients with vitiligo, these epidermalmelanocytes are gone. In some cases, there are surviving melanocytesdeeper in the skin down the hair follicles. These melanocytes may beseveral millimeters deep. UVB cannot penetrate this deep in the skin tostimulate these surviving deep melanocytes. Exposure to UVB results in asunburn at the surface of the skin with no stimulation of these deepmelanocytes. Thus attempts to repopulate the vitiligo areas withmelanocytes deep in the skin in response to UVB exposure have failed.UVA will penetrate a bit deeper in the skin than UVB. However, UVA isvery poor at stimulating melanocytes to proliferate and migrate.

DESCRIPTION OF RELATED ART

[0005] The present invention uses an excimer laser to restorepigmentation to skin areas afflicted with vitiligo, and is animprovement over current treatments for vitiligo. Currently, treatmentsfor vitiligo suffer from a number of drawbacks. For instance,Fitzpatrick's Dermatology in General Medicine, Vol. 1, Chapter 89(5^(th) ed., I. M. Freedberg et al., eds., 1999) teaches the use ofsunscreens and cosmetic cover-ups including dyes and conventional makeupas a way to mask skin areas afflicted with vitiligo. However, theability of sunscreens to minimize contrast between normal skin andvitiligo-afflicted areas has been disappointing. Sunscreens, as well ascosmetics and dyes, are not permanent. These products tend to rub-offand have been of limited value in areas such as the lower neck, wristsand hands. In addition, unlike the present invention, sunscreens andcosmetics cover-ups do not attempt to treat vitiligo, but simply blendin the affected areas with the surrounding skin. The prior art alsoteaches the use of topical glucocortoids to treat isolated areas ofvitiligo. Fitzpatrick's Dermatology in General Medicine. However, theoverall results tend to be disappointing. The present invention improveson these treatments by providing a more permanent restoration ofpigmentation to vitiligo affected areas, with a relatively high rate ofsuccess.

[0006] Another known treatment for vitiligo attempts to increase theaction of UVA light by combining exposure to UVA with a chemical that isapplied to the skin to increase sensitivity to UVA. Fitzpatrick'sDermatology in General Medicine, Vol. 1, Chapter 89 (5^(th) ed., I. M.Freedberg et al., eds., 1999). This chemical is known as psoralen, andpsoralen and UVA together are known as PUVA. Specifically, high outputUVA (320-400 nm) light bulbs are utilized within an indoor phototherapyunit. The patient applies psoralen to the effected areas, then standsinside the phototherapy unit for exposure to the UVA light emitted byconventional tube-style bulbs.

[0007] This type of PUVA treatment suffers from a number of drawbacks.Unlike the present invention, PUVA treatment is to the whole body, notjust the vitiligo areas. Therefore PUVA therapy has been associated withthe development of skin cancers. PUVA treatment is also time-consuming;a minimum of 100 treatments, given 2-3 times per week over many months,is necessary before any response is seen. In addition, this treatmenthas had a relatively low success rate. Significantly less than 50% ofpatients will respond to this treatment. The present invention, however,treats only those skin areas afflicted with vitiligo, and thus minimizesthe risk of skin cancer. The present invention also is less timeconsuming, and enjoys a relatively higher success rate.

[0008] Topical PUVA also may be used to treat localized patches ofvitiligo and consists of applying a topical preparation of8-methoxypsoralen to the patch of vitiligo and exposing the patch to UVAradiation at intervals of two to three times weekly. This type of PUVAtreatment also has a number of drawbacks. Erythema, blistering andhyperpigmentation of surrounding skin are common complications. Inaddition, the success rate is relatively low. Repigmentation is seen inonly about half of treated patients. Westernof, W., et al., “Treatmentof Vitiligo with UV-B Radiation vs. Topical Psoralen Plus UV-A,” Arch.Dermatol; 1997; 133:1525-28.

[0009] Phototherapy with UV-A radiation and oral psoralens is anotherknown treatment. UV-A irradiation occurs at intervals of two to threetimes weekly and is generally maintained for months to greater than ayear. Once again, the success rate is relatively low. Elliott, J.,“Clinical Experiences With Methosaxalen in the Treatment of Vitiligo”,J. Invest Dermatol; 1959; 32: 311-314; Farah, F. et al, “The Treatmentof Vitiligo with Psoralens and Triamcinolone By Mouth”, Br. J. Dermatol;1969; 79: 89-91; Ortonne J., “Psoralen Theraphy In Vitiligo”, Clin.Dermatol; 1989; 7:120-135. Moreover, side effects of this type of PUVAinclude burning, nausea, erythema, lentigenes, pruritus, and cataracts.

[0010] UVB phototherapy is much more effective at stimulatingmelanocytes than PUVA. However, regular UVB light cannot penetrate theskin deeper than the epidermis, and hence is completely ineffective instimulating the deep melanocytes underneath patches of vitiligo. Thepresent invention overcomes this problem in the prior art through theuse of an excimer laser which emits laser light in the ultraviolet rangeand provides higher energy fluences thereby decreasing the treatmenttime.

[0011] M. Thissen et al., Laser Treatment for Further Depigmentation inVitiligo, International Journal of Dermatology, Vol. 36 (1997) teachesthe use of a ruby laser to depigment normal skin and bleach it to awhite color. Ruby lasers, unlike excimer lasers, employ a ruby crystalto generate laser light in the red spectrum. The laser light is used todepigment normal skin, and does not attempt to restore or treat skinareas afflicted by vitiligo. Therefore, unlike the present inventionwhich attempts to stimulate melanin production and restore pigmentation,patients subjected to the Thissen treatment end up depigmenting theirremaining normal skin. The drawbacks of this treatment are that thedepigmented skin lacks melanin and is the color white, which isgenerally less aesthetically desirable than the natural skin color ofthe patient. This depigmented skin is also more sensitive to the sunthan normally pigmented skin, and the patient with depigmented skin mustbe protected from the sun for the rest of his or her life. Finally, theThissen article acknowledges that this method is only effective invitiligo afflicted patients where the skin has become over 80%depigmented.

[0012] K. Sasaki et al., Role of Low Reactive-Level Laser Therapy (LLLT)in the Treatment of Acquired and Cicatrical Vitiligo, Laser Therapy,Vol. 1 No.3 (1989) teaches use of a diode laser, either alone or incombination with an argon laser, to revive dormant or malfunctioningmelanocytes in order to repigment vitiligo afflicted skin areas. Thistechnique suffers from the disadvantage that both the argon and diodelasers are needed in order to treat cicatrical-type vitiligo, orvitiligo that follows after scarring or trauma. Argon lasers also sufferfrom the disadvantage that they may cause thermal damage to the skin. Inaddition, argon lasers as disclosed in Sasaki emit visible light (488 nmand 514.5 nm), while diode lasers emit infrared light (830 nm). Unlikethe present invention, these lasers do not emit UV light, and thereforedo not benefit from the special ability UVB light has in stimulatingmelanocyte growth and melanin production.

[0013] H. Yu et aL, Helium-Neon Laser Treatment Induces Repigmentationin Segmental-Type Vitiligo, Journal of Investigative Dermatology,Vol.112(4) (1999) teaches use of a Helium-Neon laser that emits light inthe visible red to infrared range, as opposed to UV light. Unlike thepresent invention, Helium-Neon laser light suffers from the disadvantagethat it does not stimulate melanocytes directly, but instead inducesnerve growth. For this reason, this method of treating vitiligo isconfined to segmental-type vitiligo, which is vitiligo caused bydysfunction of nerves.

[0014] Lasers have also been used to treat vitiligo to aid in skingrafting. R. Kaufman, et al., Grafting of In Vitro Cultured Melanocytesonto Laser-Ablated Lesions in Vitiligo, ACTA Demato-Veneriologica, Vol.78/2 (1998); J. S. Yang et al., Treatment of Vitiligo with AutologousEpidermal Grafting by Means of Pulsed Erbium: YAB Laser, Journal of theAmerican Academy of Dermatology, Vol. 38/2 (1998). Unlike the presentinvention, these techniques are invasive and require that the vitiligoaffected areas be relatively small and stable.

[0015] Narrowband UV-B phototherapy using a spectrum of 311-315 nmwavelength with a peak emission of 311 nm has been used to treatvitiligo. Westerhof et al. teaches the use of narrowband UV-Bphototherapy at intervals of two times per week for four to twelvemonths. However, this method requires regular phototherapy sessionsseveral times a week for up to a year to achieve a therapeutic response.UV-B phototherapy in general has few side effects and is mainly limitedto erythema.

[0016] What is needed is a method of treating vitiligo with UVB lightthat treats only the areas of vitiligo with increased precision, athigher energy fluences, to reduce length of treatment. What is alsoneeded is a method of treating vitiligo that is as effective as UVBlight in stimulating melanocytes, but without the disadvantage of beingunable to penetrate beyond the epidermal skin layer. What is also neededis a method of treating vitiligo that only treats the areas of thevitiligo, and not the entire body, to reduce the risk of skin cancers.Finally, what is needed is a method that restores pigmentation to skinareas afflicted with vitiligo, rather than simply covering the affectedareas or bleaching normal skin white, so that the result is both morepermanent and more aesthetically pleasing.

BRIEF SUMMARY OF THE INVENTION

[0017] The present invention is a method of treating vitiligo using anexcimer laser, a laser which produces light in the UVB range. Thepresent invention includes a method for treating vitiligo byincrementally increasing exposure of afflicted areas of skin with UVBlaser light to restore the pigmentation in the areas afflicted withvitiligo. The present invention overcomes the problems associated withcurrent vitiligo treatments through the use of an excimer laser. Laserlight is coherent and collimated whereas regular light is incoherent anddivergent, allowing laser UVB light to penetrate deeper into skin andquickly stimulate deep melanocytes underneath patches of vitiligo.Therefore unlike regular UVB light or, PUVA therapy, the presentinvention is able to better stimulate deep melanocytes, and is able todeliver higher energy fluences in less time than known treatments.Another advantage of the present invention is that laser treatment isconfined to only those areas afflicted with vitiligo, not to normalskin, and thus significantly reduces risk of skin cancers over othertypes of therapy such as PUVA treatments. Yet another advantage of thepresent invention is that the vitiligo areas are treated and madedarker, making the areas better match the natural skin color of thepatient, as opposed to simply bleaching the surrounding non-vitiligoareas to an unnatural white. Finally, the present invention changes theactual pigment of the skin, and therefore will not rub or wash-off.

(A) BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The patent or application file contains at least one drawingexecuted in color. Copies of this patent or patent applicationpublication with color drawing(s) will be provided by the Office uponrequest and payment of the necessary fee.

[0019]FIG. 1 depicts vitiligo involving periocular skin in an individualwith phototype V skin before treatment.

[0020]FIG. 2 depicts vitiligo involving the extensor elbow in anindividual with phototype V skin before treatment.

[0021]FIG. 3 depicts vitiligo involving the periocular skin in anindividual with phototype III skin before treatment.

[0022]FIG. 4 depicts a comparison of the number of treatments and thedegree of repigmentation in the study population.

[0023]FIG. 5 depicts complete repigmentation after 5 treatments.

[0024]FIG. 6 depicts spotty follicular repigmentation after 12treatments.

[0025]FIG. 7 depicts focal repigmentation after 12 treatments.

(B) DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention is a method of using UVB laser light totreat vitiligo. Laser light is different than regular light in that itis coherent and collimated, which can be thought of as more“concentrated.” A given dose of laser light is often much more effectivein producing photochemical reactions than conventional light. Treatmentof vitiligo with UVB laser light is superior because laser light 1)penetrates deeper in the skin than conventional light, and 2) a givendose of light is delivered much more quickly with laser light. Thissecond effect becomes important if stimulation of melanocytes has a timecomponent, i.e. stimulation is more effective if done quickly.

[0027] Also claimed and disclosed is a method of using UVB laser lightto treat vitiligo where the time of exposure to the vitiligo afflictedskin areas is gradually increased. A diagnosis of vitiligo is madeclinically, and the absence of melanin is confirmed by Woods lightexamination. A Wood's light examination uses UV light, also known as“black light,” to accentuate areas of white color. In the practicinginvention, a patient afflicted with vitiligo is treated by exposing theafflicted area to the UVB laser beam at periodic intervals. For example,the exposure to the vitiligo afflicted skin areas can be administeredbetween 1 to 5 times per week. The first treatment would last for up to5 seconds, depending on the intensity setting of the laser beam. Thegreater the intensity, the shorter the exposure to the beam. Theexposure time for each treatment would be gradually increased, to amaximum of 10 seconds.

[0028] In one embodiment of the invention, an excimer laser is used togenerate the UVB laser light. An excimer laser is a laser which uses arare-gas halide or rare-gas metal vapor and emits laser light in theultraviolet (126 to 558 nm) range. Currently, only excimer lasers emitlaser light in the UV range, although any future lasers that emit lightin the UVB range would also be encompassed by this invention. The laserused should operate in a range between 290 and 320 nm in wavelength, theUVB range of light. The laser should be utilized at a setting of notmore than 120 mwatts.

[0029] A 308 excimer laser from the Surgilight Corporation, Winter ParkFlorida, is preferred for use in practicing the present invention. Thislaser operates at 308 nm via a fiber optic cable with pulse duration of120 nsec, fired at repetition rate of 20 hz. The laser spot size is10×10 mm. A photometer measures laser output, and the laser is utilizedat a setting of 60 mwatts. In one preferred method of treatment, apatient with vitiligo is exposed to the 308 nm excimer laser three timesa week. The first treatment lasts 2 seconds. The patient returns, and ifthere is no sunburn, the treated area is retreated again for 2 seconds.If there is sunburn, treatment is withheld until the sunburn is gone. Onthe third visit, if there is no sunburn, the dose is increased to 4seconds. This is repeated the fourth visit, and then increased to 6seconds on the fifth visit. On the sixth visit, 6 seconds is givenagain. Therefore, in this preferred method, each dose is repeated once,then increased by two seconds, to a maximum of 10 seconds. Treatment iscontinued for one month, or until repigmentation occurs, which is a muchshorter time than PUVA therapy, which typically takes 6 months beforeany result is seen. Repigmentation is the appearance of brown pigment inthe treated area, and is documented by standardized photography. Inpreliminary trials, four out of five patients receiving treatment for aminimum of nine sessions showed some response. This is a significant andsubstantial improvement in success rate over PUVA, glucocortoids, or anyother current therapy for vitiligo. The repigmented skin is alsorelatively more permanent than other treatments such as sunscreens andcosmetic cover-ups, and will not rub-off.

[0030] When compared to standard phototheraphy, the 308 nm excimer laserhas the advantage of having increased precision and the ability todeliver higher energy fluences thereby decreasing treatment time.

EXAMPLES

[0031] The following are intended as non-limiting examples of theinvention.

[0032] Six men and twelve women with multiple discreet chronic stablepatches of vitiligo enrolled in the study. Most patients had receivedand failed a variety of prior therapies for vitiligo (Table 1). Nopatient received any additional vitiligo therapy for at least one monthprior to and during the study.

[0033] Eighteen patients started the study with a total of twenty-ninetreated vitiligo patches. All patients had untreated vitiligo patchesthat were used as controls. Test areas of vitiligo were treated using a308-nm xenon chloride excimer laser. A 120-ns, 20-hz, pulse was usedwith a 10-mm by 10-mm spot size and a power output of 60 mw of laserlight. Lesions were treated three times a week for a maximum of 12treatments. Exposure time was started at 2 seconds and increased by 2seconds at every other visit until complete repigmentation occurred oruntil the protocol (12 treatments) was completed. Treatment was withheldif sunburn was observed and held until resolution.

[0034] Treated areas were evaluated for repigmentation and erythema onseparate four point scales. Repigmentation was graded on the percentageof treated area of repigmentation as follows: 0:0%, 1:1-25%, 2:26-75%and 3:76-100%. Sunburn (erythema) was similarly graded as follows:0—None, 1—Mild, 2—Moderate, 3—Severe. Patients with no repigmentationwere defined as non-responders.

[0035] Results

[0036] Twelve patients with 23 patches completed at least sixtreatments. Six patients with 11 patches of vitiligo completed alltwelve treatments that required an average of four weeks to complete.Six patients dropped out of the study before completion of sixtreatments and resulted in one slight repigmentation and fivenon-responders. Two of the non-responders developed mild erythema.Twelve patients with six or more total treatments of 23 vitiligo patchesresulted in partial repigmentation in 57% of twenty-three patches. Sixpatients who completed twelve treatments of 11 vitiligo patches resultedin partial repigmentation in 87% of eleven patches (FIG. 4). There wereno serious adverse events. Mild sunburn with persistent erythema lastingup to three weeks was observed in some patients. Patients with the mostrepigmentation were skin-types III-VI. Table 1 sets forth the results.TABLE 1 Demographics and Study Results of Patients Involved In theProtocol Skin Prior Treatment Treatments % Repig- Patient Sex PhototypeTreatment Locations Received mentation* Erythema** 1 M V TS Periocular 53 0 Forearm 12 3 0 2 F III PUVA Periocular 12 1 0 Back 12 1 0 Hand 12 00 Thigh 12 1 0 3 F I None L. Forearm 12 1 1 4 F III-IV None L.Preauricular 9 5 M II None L. Neck 3 0 1 6 F II TS. Folate L. Hand 5 1 07 F IV PUVA Finger 12 0 0 8 M II TS Abdomen 3 0 1 9 F VI TS R. Temple 20 0 10 F II None R. Wrist 6 11 F III-IV None R. Axilla 8 1 1 Sternum 8 11 12 F None R. Axilla 1 0 0 13 M III-IV None Chin 10 0 1 L. Elbow 10 0 1L. Arm 10 0 1 14 M II PUVA L. periocular 10 0 1 R. Elbow 10 1 0 Chin 100 1 15 F II PUVA L. Shin 9 1 0 L. Elbow 9 0 1 16 F II TS Forearm 5 0 017 M IV PUVA Forehead 12 1 0 Chin 12 1 0 18 F V None Elbow 12 2 0

[0037] While the invention has been particularly shown and describedwith reference to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the spirit and scope of theinvention. All patent applications, patents, patent publications andliterature references cited in this specification are herebyincorporated by reference in their entirety.

What is claimed is:
 1. A method of treating vitiligo comprising thesteps of; (A) identifying an area of skin with an absence of melanin,(B) repeatedly exposing said area of skin to laser light in the UVBrange.
 2. The method of claim 1 wherein said laser light is generated byan excimer laser.
 3. The method of claim 2 wherein the wavelength ofsaid laser light is 308 nm, and the intensity of said laser light is 60mwatts.
 4. The method of claim 1 wherein the wavelength of said laserlight is 290 to 320 nm.
 5. The method of claim 4 wherein the intensityof said laser light is not more than 120 mwatts.
 6. The method of claims3 and 5 wherein said area of skin is exposed 1-5 times a week.
 7. Themethod of claim 3 wherein said area of skin is exposed at least 3 timesa week.
 8. The method of claim 6 wherein said area of skin is exposed tosaid laser light for not more than 5 seconds during the first exposure,and the exposure time is then gradually increased to a maximum of 1 0seconds per exposure.
 9. The method of claim 7 wherein said area of skinis exposed to said laser light for 2 seconds during the first exposure,and the exposure time then increased by 2 seconds after every twoexposures.
 10. A method of treating vitiligo comprising the steps of;(A) identifying an area of skin with an absence of melanin, (B) firstexposing said area of skin to UVB laser light for 1-5 seconds, (C)increasing the length of exposure of said area of skin by 1-3 secondsafter every two exposures until said area of skin is repigmented. 11.The method of claim 10 wherein the UVB laser light is generated by anexcimer laser.
 12. The method of claim 11 wherein the wavelength of saidlaser light is 308 nm, and the intensity of said laser light is 60mwatts.
 13. The method of claim 10 wherein the wavelength of said laserlight is 290-320 nm.
 14. The method of claim 13 wherein the intensity ofsaid laser light is not more than 120 mwatts.
 15. The method of claim 14wherein said area of skin is exposed 1-5 times a week.
 16. The method ofclaim 1 2 wherein said area of skin is exposed at least 3 times a week.